High-dose Exposure Research Articles

High-dose folic acid use and cancer risk in women who have given birth: A register-based cohort study.

This study was undertaken to study whether high-dose folic acid (>1 mg daily) use is associated with an increased risk of cancer in all women who have given birth and in women with epilepsy. High-dose folic acid supplementation during pregnancy has been linked to increased cancer risk in children born to mothers with epilepsy. We identified women with their first pregnancy in Denmark (1997-2017), Norway (2005-2017), and Sweden (2006-2017) using medical birth registers, linking individual data across nationwide health registers and statistical agencies. Exposure was defined as filled prescriptions for high-dose folic acid, considered time-varyingly. The primary outcome was the first malignant cancer diagnosis. Hazard ratios (HRs) of cancer after high-dose folic acid exposure were estimated using Cox proportional hazard models with 95% confidence intervals (CIs), adjusted for confounders including antiseizure medication (ASM) use, and stratified by maternal epilepsy diagnosis. A 6-month time lag was applied, as cancer is unlikely to develop immediately. With up to 21 years of follow-up, we identified 1 465 785 women who gave birth, including 64 485 (4.4%) exposed to high-dose folic acid. In the exposed group, 755 cancer cases were observed (208 per 100 000 person-years, 95% CI = 193.8-223.5), compared with 18 702 cases in the unexposed group (164 per 100 000 person-years, 95% CI = 161.5-166.2), yielding a 20% increased cancer risk overall (adjusted HR = 1.2, 95% CI = 1.1-1.2). This risk was attenuated after the 6-month lag analysis (adjusted HR = 1.1, 95% CI = 1.04-1.2). The risk for non-Hodgkin lymphoma was increased in all analyses (n = 28, adjusted HR = 2.0, 95% CI = 1.3-2.9). The association between high-dose folic acid use and overall cancer risk was similar in those with epilepsy regardless of ASM use (adjusted HR = 1.3, 95% CI = 1.0-1.8). High-dose folic acid use was associated with increased overall cancer risk in women who have given birth, with a consistent association with non-Hodgkin lymphoma, including those with epilepsy, regardless of ASM use.

Attempt to re-estimate organ doses of victims in non-homogeneous exposure accident by means of the state-of-the-art Mesh-type Reference Computational Phantom-a case study of an IR-192 source accident.

An attempt was made to estimate organ doses of a victim in a high-dose non-homogeneous exposure accident caused by a sealed 192Ir gamma-ray source. The Gilan accident was selected as a case study. Organ doses including testis, red bone marrow and so on were properly estimated by applying the Monte Carlo calculation with the state-of-the-art adult male Mesh type Reference Computational Phantom. By introducing a complicated exposure scenario, the dose distribution on the right chest of the victim in the Gilan accident could be reproduced to a certain extent.

Solar ultraviolet radiation exposure of trail runners in an ultraendurance competition at high altitude

BackgroundOutdoor sports are associated with overexposure to solar ultraviolet radiation and sunburn. AimsTo quantify solar ultraviolet radiation (UVR) exposure received by trail runners during an ultraendurance competition at high altitude and to assess their sun exposure habits, sun protection behaviors, and attitudes and knowledge regarding skin cancer. MethodsTrail runners taking part in the 2023 Ultra Sierra Nevada race (Spain, April 14–16, 2023) completed an online validated questionnaire on sun-related habits, behaviors, attitudes, and knowledge. Environmental conditions such as temperature, relative humidity, and UVR as well as participants’ personal erythemal dose were measured during the competition. ResultsThe average ambient cumulative erythemal dose ranged from 59.9 to 19.3 standard erythemal doses (SED) and the mean effective radiation received by the athletes studied (n = 17) ranged from 24.2 to 7.6 SED in the Extreme (154 km) to Half-Marathon (25.1 km) races. The questionnaire was completed by 194 athletes (mean age 41.3 ± 8.9 years; 76.8 % men). A total of 22.4 % of athletes surveyed reported skin phototype I-II. Two-thirds (66.5 %) had sunburn after doing outdoor sports in the previous year. In regard to photoprotection practices while exercising outdoors, 62.6 % reported wearing a hat/cap, 59.2 % avoided the midday sun, 38.7 % used sunscreen with sun protection factor ≥ 15, and 49.7 % stated they did not reapply sunscreen. ConclusionsThe trail runners studied received a high solar exposure dose during the competition. Future interventions are needed to improve individual and organizational photoprotection measures in trail-running events to reduce the risk of skin cancer.

Repeated high-dose esketamine in early postnatal rats leads to behavioural deficits with long-term modifications in white matter microstructural integrity

Esketamine is commonly used for sedation or general anaesthesia in infants and young children. However, repeated esketamine administration during periods of rapid brain growth and development may result in various pathophysiological and cognitive changes. Therefore, this study aimed to investigate the influence of recurrent esketamine exposure on long-term behavioural and white matter consequences. Seven-day-old (P7) male rats were allocated to control, high-, and low-dose groups. Behavioural paradigm assessment was conducted at P25–29. Diffusion tensor imaging revealed long-term effects on water diffusivity in the splenium and cingulum white matter of the corpus callosum at P30. Subsequent two-dimensional structure-tensor analysis of brain tissue sections stained with Luxol fast blue (LFB) showed marked changes in the white matter microstructure in rats after multiple exposures to varying esketamine doses. High-dose esketamine significantly reduced activity time and total distance in the open-field experiment. High-dose esketamine exposure might lead to impaired short-term memory in rats. Additionally, the high-dose group showed prolonged immobility time during the forced swimming test. On the balance beam, the high-dose group displayed more right turns and right-foot slips and lower time spent on the rotating bar, indicating motor defects, than did the other groups. Diffusion tensor imaging demonstrated a decreased water molecule diffusion ability in the corpus callosum in the high-dose group. LFB staining indicated microstructural differences in the white matter of animals in the high-dose group. These findings suggest that behavioural deficits in high-dose esketamine-treated rats are at least partially attributed to changes in the white matter microstructure.

Application of FISH based G2-PCC assay for the cytogenetic assessment of high radiation dose exposures: Potential implications for rapid triage biodosimetry.

The main goal of this study is to test the utility of calyculin A induced G2-PCC assay as a biodosimetry triage tool for assessing a wide range of low and acute high radiation dose exposures of photons. Towards this initiative, chromosome aberrations induced by low and high doses of x-rays were evaluated and characterized in G2-prematurely condensed chromosomes (G2-PCCs) by fluorescence in situ hybridization (FISH) using human centromere and telomere specific PNA (peptide nucleic acid) probes. A dose dependent increase in the frequency of dicentric chromosomes was observed in the G2-PCCs up to 20 Gy of x-rays. The combined yields of dicentrics and rings in the G2-PCCs showed a clear dose dependency up to 20 Gy from 0.02/cell for 0.1 Gy to 14.98/cell for 20 Gy. Centric rings were observed more frequently than acentric ring chromosomes in the G2-PCCs at all the radiation doses from 1 Gy to 20 Gy. A head-to-head comparison was also performed by FISH on the yields of chromosome aberrations induced by different doses of x-rays (0 Gy -7.5 Gy) in colcemid arrested metaphase chromosomes and calyculin A induced G2-PCCs. In general, the frequencies of dicentrics, rings and acentric fragments were slightly higher in G2-PCCs than in colcemid arrested metaphase chromosomes at all the radiation doses, but the differences were not statistically significant. To reduce the turnaround time for absorbed radiation dose estimation, attempt was made to obtain G2-PCCs by reducing the culture time to 36 hrs. The absorbed doses estimated in x-rays irradiated (0,1,2 and 4 Gy) G2-PCCs after 36 hrs of culture were grossly like that of G2-PCCs and colcemid arrested metaphase chromosomes prepared after 48 hrs of culture. Our study indicates that the shortened version of calyculin A induced G2-PCC assay coupled with the FISH staining technique can serve as an effective triage biodosimetry tool for large-scale radiological/nuclear incidents.

Lower-dose vs high-dose oral bisphenol S action of lipid metabolism in liver of male SD rat via mediating different SREBP isoforms

Bisphenol S (BPS) is commonly used for the industrial production of thermal paper, polycarbonate plastics, epoxy resins and other materials. Studies have reported that BPS can lead to triglyceride (TAG) or/and cholesterol (CHO) accumulation in the liver in zebrafish and mice, but the reasons for the different types of lipids that accumulate in the liver following BPS exposure are unclear. Here, the influences of lower-dose (10 mg/kg body weight/day) and high-dose (50 mg/kg body weight/day) BPS exposure to male SD rats on the accumulation of different lipids in the liver were explored. The results indicated that BPS treatment increased the levels of acetyl-CoA and glycogen in the liver. A lower dose of BPS upregulated the mRNA and protein expression levels of sterol regulatory element-binding protein 1 (srebp1), which is involved in the de novo synthesis of TAG in the liver, thus promoting the synthesis of glycerides (diacetylglyceride and TAG). However, a higher dose of BPS induced CHO accumulation, but inhibited the mRNA expression of genes (i.e., srebp2, hmgcr and hmgcs) involved in the de novo synthesis of CHO in the liver. Excessive accumulation of glycerides and CHO led to destruction of the physiological structure of rat liver, causing disorders in liver function. Our data provide new insight into the different mechanisms by which glyceride and CHO accumulate in the liver after BPS exposure.

MIIST305 mitigates gastrointestinal acute radiation syndrome injury and ameliorates radiation-induced gut microbiome dysbiosis.

High-dose radiation exposure results in gastrointestinal (GI) acute radiation syndrome identified by the destruction of mucosal layer, intestinal epithelial barrier dysfunction, and aberrant inflammatory responses. In addition, radiation causes gut microbiome dysbiosis characterized by diminished microbial diversity, reduction in the abundance of beneficial commensal bacteria, and the spread of bacterial pathogens that trigger the recruitment of immune cells and the production of pro-inflammatory factors that lead to further GI tissue damage. Currently, there are no FDA- approved countermeasures that can treat radiation-induced GI injury. To meet this critical need, Synedgen Inc ., has developed a glycopolymer radiomitigator (MIIST305) that is specifically targeted to the GI tract which acts by intercalating into the mucus layer and the glycocalyx of intestinal epithelial cells that could potentially ameliorate the deleterious effects of radiation. Male C57BL/6J adult mice were exposed to 13 Gy total body X-irradiation with 5% bone marrow shielding and MIIST305 was administered on days 1, 3, and 5 post-irradiation. Approximately 85% of the animals survived the irradiation exposure and were apparently healthy until the end of the 30-day study period. In contrast, no control, vehicle-treated animals survived past day 10 at this radiation dose. We show that MIIST305 improved intestinal epithelial barrier function and suppressed systemic inflammatory response mediated by radiation-induced pro-inflammatory cytokines. Taxonomic profiling and community structure of the fecal and colonic mucosa microbiota demonstrated that MIIST305 treatment increased microbial diversity and restored abundance of beneficial commensal bacteria, including Lactobacillus and Bifidobacterium genera, while suppressing potentially pathogenic bacteria compared with vehicle-treated animals. In summary, MIIST305 is a novel GI-targeted therapeutic that greatly enhances survival in mice exposed to lethal radiation and protects the GI tract from injury by restoring a balanced gut microbiota and effectively reducing proinflammatory responses. Further development of this drug as an FDA-approved medical countermeasure will be of critical importance in the event of a radiation public health emergency.

Effect of co-exposure to multiple metals (Pb, Cd, Cr, Hg, Fe, Mn and Ni) and metalloid (As) on liver function in Swiss albino mice.

The study examined the cumulative toxic effect of multiple elements, As, Pb, Cd, Cr, Hg, Fe, Mn and Ni on the liver function and their association with inflammation and apoptosis. To explore the health consequence of simultaneous exposure to multiple metals and metalloid, male and female Swiss Albino mice were randomly divided into 14 groups and subjected to different doses [MPL (maximum permissible limit), 1×, 5×, 10×, 50× or 100×] of metal(loid)s mixture via drinking water for 8weeks. Data showed that combined effect of multiple elements impaired the liver function. This was associated with significant decrease in the antioxidant enzymes and the elevation in lipid peroxidation for high exposure dose of 50× and 100× (p < 0.05). The metal(loid)s mixture exposure led to significant increase (p < 0.05) in cytokines, TNF-α, IL-6 and effector caspases (3 and 6) in exposure groups above 10× dose. Histopathological observation also revealed significant damage in the hepatic tissue on exposure to high dose. Dose dependent accumulation of respective elements (As, Cd, Cr, and Pb) in the liver was observed in each of the exposure groups. However, similar dose related increment was not observed for essential metals such as Ni, Fe and Mn. Differential accumulation of metals in the liver may be attributed to the effect of co-contaminant exposure, which could affect the divalent cation absorption due to antagonism and competitive transport process. Overall findings in this study manifest the complexity of possible joint effect of co-exposure to multiple metals and metalloid on the liver function.

Lysosomal disruption, mitochondrial impairment, histopathological and oxidative stress in rat's nervous system after exposure to a neonicotinoid (imidacloprid).

Imidacloprid (IMI), a neonicotinoid pesticide, has been widely used due to its high efficiency against insect pests. However, its prolonged exposure may pose significant risks to non-target organisms, including mammals. Recent studies have raised concerns about its potential neurotoxicity, yet the underlying mechanisms remain poorly understood. This study aimed to assess the neurotoxic effects of chronic Imidacloprid exposure in Wistar rats, focusing on oxidative stress, mitochondrial dysfunction, and lysosomal disruption. Wistar rats were orally administered two doses of Imidacloprid (5mg/kg and 50mg/kg body weight) for three months. Neurotoxic effects were assessed by measuring key biochemical markers such as the enzymatic activities of catalase (CAT), glutathione peroxidase (GPx), superoxide dismutase (SOD), and glutathione S-transferase (GST). Non-enzymatic markers, including glutathione (GSH) levels and malondialdehyde (MDA) index, were also evaluated. Mitochondrial function was assessed by analyzing oxygen consumption, swelling, and membrane permeability and histopathological changes. Lysosomal stability was examined using the Neutral Red Retention Time (NRRT) assay. Neutral red is a dye that accumulates in the acidic environment of lysosomes. Healthy lysosomes retain the dye, while compromised lysosomes lose it, indicating destabilization. By measuring the amount of neutral red retained in lysosomes, the NRRT assay assesses lysosomal integrity. Lysosomal pH variations were also monitored to evaluate functional changes. Microscopic analysis provided insight into structural changes in lysosomes and other cell components. Lysosomal destabilization was further confirmed by morphological alterations observed through light microscopy, revealing a progressive, time-dependent degeneration of lysosomal structures, including lysosomal expansion, neutral red dye leakage, and cell rounding. These changes reflected a temporal evolution of lysosomal damage, progressing from minor structural disruptions to more severe alterations as exposure continued, observable at the microscopic level. During the study, clinical observations of intoxicated rats included symptoms such as lethargy, reduced activity levels, and impaired motor coordination. High-dose Imidacloprid exposure led to noticeable behavioral changes, including decreased exploratory behavior and altered grooming patterns. Additionally, signs of neurotoxic effects, such as tremors or ataxia, were observed in the rats exposed to the higher dose, reflecting the systemic impact of chronic pesticide exposure. The results revealed a significant decrease in the enzymatic activities of CAT, GPx, and SOD, accompanied by an increase in GST activity. A notable reduction in glutathione levels and a rise in MDA index were observed, indicating enhanced oxidative stress in the brain. Mitochondrial impairment was evidenced by disturbances in oxygen consumption, increased swelling, and altered membrane permeability. Lysosomal destabilization was confirmed by reduced retention of neutral red dye, structural changes in lysosomes, and a significant rise in lysosomal pH in the IMI-exposed groups. In addition, the histopathological features indicate that imidacloprid at the given dose and exposure duration may have caused notable neurotoxic effects in Wistar rat brain tissue. Chronic exposure to Imidacloprid induces oxidative stress, mitochondrial dysfunction, lysosomal disruption and histopathological alterations in the central nervous system of Wistar rats. These findings provide valuable insights into the neurotoxic mechanisms of neonicotinoid pesticides, highlighting the need for further research to understand the long-term effects of Imidacloprid exposure on mammalian health.

Selenium-containing peptides as effective alleviators for low-level lead induced neural damage

The TSeMMM and SeMDPGQQ, two selenium-containing peptides derived from Se-enriched rice protein hydrolysates, have previously been demonstrated to show neuroprotective properties against high-dose lead exposure. However, the potential toxicological effects of these functional peptides on low-dose lead-induced neurotoxicity remain poorly understood. The present study aimed to investigate the protective mechanism of two selenium-containing peptides in mitigating low-dose Pb2+-induced damage in HT22 cells. Results showed that treatment with 40 μmol/L Pb2+ significantly reduced cell viability and increased apoptosis, both of which were alleviated by 40 μmol/L TSeMMM and SeMDPGQQ treatment. Furthermore, two peptides exhibited antioxidant potentials by reducing reactive oxygen species levels to 32.19% and 79.29% of the model group, respectively. They also enhanced antioxidant enzyme activities and mitigated oxidative stress through activation of the Keap1/Nrf2 pathway. Additionally, two peptides improved mitochondrial function by elevating mitochondrial membrane potential, ATP production while dramatically reducing reactive oxygen species levels. Interestingly, TSeMMM exhibited superior neurointerventional effects compared to SeMDPGQQ. The RNA sequencing analysis revealed that TSeMMM modulated gene expressions related to oxidative stress and neuroprotective function. The study provides insights into the protective mechanism underlying selenium-containing peptides for mitigating neuronal damage.

Integration methods: H3PO4 immersion and gamma irradiation exposure in modified activated carbon from banana (Musa paradisiaca L. sp.) stems biomass

Abstract Indonesia has abundant natural resources or tropical fruit like bananas (Musa paradisiaca L.sp.). Waste from natural resources can be identified as biomass. In Musa paradisiaca L.sp., biomass is derived from banana peels, stems, and leaves. This biomass can be used as activated carbon. Banana stems can be processed into activated carbon because they contain galacturonic acid. This a combine method of chemical activation via phosphate acid (H3PO4) immersion and gamma irradiation exposure to synthesize activated carbon from banana stems. These combined methods can make the surface area increase and make its function improve. Gamma irradiation exposure used variant doses 10 kGy, 30 kGy, and 50 kGy. Synthesized activated carbon was characterized using Teller Brunauer Emmett (BET) to analyze surface area of Activated Carbon and to identify the functional groups using Fourier Transform Infrared Spectroscopy (FTIR). The result shows the hidroxyl functional group decreases, and the transmission between irradiated carbons decreases with the increasing irradiation dose used. Effect of integration methods of acid immersion and gamma irradiation exposure on increasing surface area is enlarger of activated carbon banana stem. However, high-dose gamma irradiation exposure did not significantly impact surface area formation.

Comparing robust proton versus online adaptive photon radiotherapy for short-course treatment of rectal cancer

Background and purposeImage-guided proton beam therapy (IG-PBT) and cone-beam CT (CBCT)-based online adaptive photon radiotherapy (oART) have potentials to restrict radiation toxicity. They are both hypothesised to reduce therapy limiting bowel toxicity in the multimodality treatment of locally advanced rectal cancer (LARC). This study aimed to quantify the difference in relevant dose-volume metrics for these modalities. Material and MethodsSix-degrees-of-freedom IG-PBT and oART short-course radiotherapy (SCRT) were simulated for 18 LARC patients. Relative biological effectiveness (RBE) was 1.1 for IG-PBT. Delivered dose was evaluated using post-CBCTs. Target coverage was considered robust if average dose to 99 % of the clinical target volume was ≥ 95 % of the prescription. Organ at risk (OAR) doses were compared using dose-volume histograms and severe bowel toxicity estimated using dose–response modelling. ResultsTarget coverage was robust in all patients for oART and all but one patient for IG-PBT. For the main OARs, IG-PBT increased the volume exposed to ≥ 15 Gy (RBE), but reduced volumes exposed to lower doses. Both low- and high-dose exposure to bowel loops were significantly different between the modalities (median (interquartile range) IG-PBT-V8.9Gy(RBE) = 92 cm3 (51–156), oART-V8.9Gy(RBE) = 166 cm3 (107–234), p < 0.001; IG-PBT-V23Gy(RBE) = 62 cm3 (25–106), oART-V23Gy(RBE) = 38 cm3 (18–75), p < 0.001), translating into similar total grade ≥ 3 bowel toxicity risk. ConclusionIG-PBT and oART delivered comparable and satisfying target coverage in SCRT for LARC with similar estimated risk of severe bowel toxicity. Volumes of OAR exposed to 15 Gy (RBE) or more were reduced by oART, while IG-PBT reduced the volumes receiving doses below this level.

Radiation protection of sodium alginate and its regulatory effect on intestinal microflora in mice

Prolonged or high-dose exposure to ionizing radiation (IR) can cause damage to normal tissues of the body. Therefore, it is imperative to find effective radiation protective agents to mitigate IR-induced damage. This study evaluated the effects of sodium alginate (SA) on the radiation protection and modulatory effects of gut microorganisms using a 60Coγ-induced damage model in mice. Results showed that SA could reduce the damage of hematopoietic system; and alleviate the oxidative damage in irradiated mice by inhibiting the content of malondialdehyde (MDA) and increasing the activities of superoxide dismutase (SOD) and glutathione (GSH) in serum, spleen, jejunum and liver. Moreover, SA treatment ameliorated IR-induced small intestine lesions and alleviated liver injury. This was consistent with decreased levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and tumor necrosis factor-α (TNF-α), and increased levels of interferon-γ (IFN-γ) and interleukin-2 (IL-2) after SA treatment. Furthermore, SA treatment reversed IR-induced gut dysbiosis, elevated the Firmicutes/Bacteroidetes ratio, increased the beneficial bacteria and reduced the pathogenic bacteria in the small intestine. In conclusion, the present study demonstrated that SA exerted good radioprotective effect by improving hematopoietic system, alleviating oxidative stress, attenuating liver injury and inflammatory response, and modulating the intestinal microbiota in irradiated mice.

Langerhans cells orchestrate apoptosis of DNA-damaged keratinocytes upon high-dose UVB skin exposure.

Ultraviolet (UV) irradiation of the skin causes mutations that can promote the development of melanoma and nonmelanoma skin cancer. High-dose UVB exposure triggers a vigorous skin reaction characterized by inflammation resulting in acute sunburn. This response includes the formation of sunburn cells and keratinocytes (KC) undergoing programmed cell death (apoptosis) when repair mechanisms of DNA damage are inadequate. The primary objective of this research was to clarify the involvement of Langerhans cells (LC) in the development of acute sunburn following intense UVB skin irradiation. To address this, we subjected the dorsal skin of mice to a single high-dose UVB exposure and analyzed the immediate immune response occurring within the skin tissue. Acute sunburn triggered an activation of LC, coinciding with a rapid influx of neutrophils that produced TNF-α. Furthermore, our investigation unveiled a marked increase in DNA-damaged KC and the subsequent induction of apoptosis in these cells. Importantly, we demonstrate a crucial link between the inflammatory cascade, the initiation of apoptosis in DNA-damaged KC, and the presence of LC in the skin. LC were observed to modulate the chemokine response in the skin following exposure to UVB, thereby affecting the trafficking of neutrophils. Skin lacking LC revealed diminished inflammation, contained fewer TNF-α-producing neutrophils, and due to the prevention of apoptosis induction, a lingering population of DNA-damaged KC, presumably carrying the risk of enduring genomic alterations. In summary, our results underscore the pivotal role of LC in preserving the homeostasis of UVB-irradiated skin. These findings contribute to a deeper understanding of the intricate mechanisms underlying acute sunburn responses and their implications for UV-induced skin cancer.

Drosophila melanogaster as a tractable eco-environmental model to unravel the toxicity of micro- and nanoplastics

Micro- and nanoplastics have emerged as pervasive environmental pollutants with potential ecotoxicological impacts on various organisms, including the model organismDrosophila melanogaster. Here we comprehensively synthesize current research on the adverse effects of micro- and nanoplastics onDrosophila, highlighting key findings and identifying gaps in the literature. Micro- and nanoplastics can lead to physical damage, oxidative stress, inflammation, genotoxicity, epigenetic changes, apoptosis, and necrosis inDrosophila. Exposure to plastic debris affects nutrient absorption, energy metabolism, and reproductive health, often in a sex-specific manner. For instance, male flies are generally more susceptible to the toxic effects of polystyrene microplastics than female flies, showing greater mortality and metabolic disruptions. Furthermore, the combined exposure of plastics with heavy metals can exacerbate toxic effects, leading to enhanced oxidative stress, genotoxicity, and gut damage. While antagonistic effects have been identified particularly with silver compounds, where polystyrene microplastics reduce the bioavailability and toxicity of silver. The adverse effects of plastic particles onDrosophiladepend on size, with smaller particles penetrating deeper into tissues and eliciting stronger toxic responses. The chemical composition of the plastics and the presence of additives also play crucial roles in determining toxicity levels. Chronic exposure to low levels can be as harmful as acute high-dose exposure, highlighting the need for comprehensive, long-term studies to fully understand the ecological and biological impacts of plastic pollution.

Adverse Events in Studies of Classic Psychedelics: A Systematic Review and Meta-Analysis.

A clear and comprehensive understanding of risks associated with psychedelic-assisted therapy is necessary as investigators extend its application to new populations and indications. To assess adverse events (AEs) associated with classic psychedelics, particularly serious AEs (SAEs) and nonserious AEs (NSAEs) requiring medical or psychiatric evaluation. The search for potentially eligible studies was conducted in the Scopus, MEDLINE, PsycINFO, and Web of Science databases from inception through February 8, 2024. Two independent reviewers screened articles of classic psychedelics (lysergic acid diethylamide [LSD], psilocybin, dimethyltryptamine [DMT], and 5-methoxy-N,N-dimethyltryptamine [5-MeO-DMT]) involving administration in clinical or research contexts. AE data were extracted and synthesized by 2 reviewers and were used for random-effects meta-analysis of AE frequency and heterogeneity. Risk of bias assessment focused on AE ascertainment (eg, systematic assessment and quality of follow-up). A hybrid approach was used for capture of all reported AEs following high-dose classic psychedelic exposure and confirmatory capture of AEs of special interest, including suicidality, psychotic disorder, manic symptoms, cardiovascular events, and hallucinogen persisting perception disorder. AEs were stratified by timescale and study population type. Forest plots of common AEs were generated, and the proportions of participants affected by SAEs or NSAEs requiring medical intervention were summarized descriptively. A total of 214 unique studies were included, of which 114 (53.3%) reported analyzable AE data for 3504 total participants. SAEs were reported for no healthy participants and for approximately 4% of participants with preexisting neuropsychiatric disorders; among these SAEs were worsening depression, suicidal behavior, psychosis, and convulsive episodes. NSAEs requiring medical intervention (eg, paranoia, headache) were similarly rare. In contemporary research settings, there were no reports of deaths by suicide, persistent psychotic disorders, or hallucinogen persisting perception disorders following administration of high-dose classic psychedelics. However, there was significant heterogeneity in the quality of AE monitoring and reporting. Of 68 analyzed studies published since 2005, only 16 (23.5%) described systematic approaches to AE assessment, and 20 studies (29.4%) reported all AEs, as opposed to only adverse drug reactions. Meta-analyses of prevalence for common AEs (eg, headache, anxiety, nausea, fatigue, and dizziness) yielded comparable results for psilocybin and LSD. In this systematic review and meta-analysis, classic psychedelics were generally well tolerated in clinical or research settings according to the existing literature, although SAEs did occur. These results provide estimates of common AE frequencies and indicate that certain catastrophic events reported in recreational or nonclinical contexts have yet to be reported in contemporary trial participants. Careful, ongoing, and improved pharmacovigilance is required to understand the risk and benefit profiles of these substances and to communicate such risks to prospective study participants and the public.

Prior exposure to pathogens augments host heterogeneity in susceptibility and has key epidemiological consequences.

Pathogen epidemics are key threats to human and wildlife health. Across systems, host protection from pathogens following initial exposure is often incomplete, resulting in recurrent epidemics through partially-immune hosts. Variation in population-level protection has important consequences for epidemic dynamics, but how acquired protection influences inter-individual heterogeneity in susceptibility and its epidemiological consequences remains understudied. We experimentally investigated whether prior exposure (none, low-dose, or high-dose) to a bacterial pathogen alters host heterogeneity in susceptibility among songbirds. Hosts with no prior pathogen exposure had little variation in protection, but heterogeneity in susceptibility was significantly augmented by prior pathogen exposure, with the highest variability detected in hosts given high-dose prior exposure. An epidemiological model parameterized with experimental data found that heterogeneity in susceptibility from prior exposure more than halved epidemic sizes compared with a homogeneous population with identical mean protection. However, because infection-induced mortality was also greatly reduced in hosts with prior pathogen exposure, reductions in epidemic size were smaller than expected in hosts with prior exposure. These results highlight the importance of variable protection from prior exposure and/or vaccination in driving population-level heterogeneity and epidemiological dynamics.

CYP2E1 in 1,4-dioxane metabolism and liver toxicity: insights from CYP2E1 knockout mice study.

1,4-Dioxane (DX), an emerging water contaminant, is classified as a Group 2B liver carcinogen based on animal studies. Understanding of the mechanisms of action of DX liver carcinogenicity is important for the risk assessment and control of this environmental pollution. Previous studies demonstrate that high-dose DX exposure in mice through drinking water for up to 3 months caused liver mild cytotoxicity and oxidative DNA damage, a process correlating with hepatic CYP2E1 induction and elevated oxidative stress. To access the role of CYP2E1 in DX metabolism and liver toxicity, in the current study, male and female Cyp2e1-null mice were exposed to DX in drinking water (5000 ppm) for 1 week or 3 months. DX metabolism, redox and molecular investigations were subsequently performed on male Cyp2e1-null mice for cross-study comparisons to similarly treated male wildtype (WT) and glutathione (GSH)-deficient Gclm-null mice. Our results show that Cyp2e1-null mice of both genders were resistant to DX-induced hepatocellular cytotoxicity. In male Cyp2e1-null mice exposed to DX for 3 months, firstly, DX metabolism to β-hydroxyethoxyacetic acid was reduced to ~ 36% of WT levels; secondly, DX-induced hepatic redox dysregulation (lipid peroxidation, GSH oxidation, and activation of NRF2 antioxidant response) was substantially attenuated; thirdly, liver oxidative DNA damage was at a comparable level to DX-exposed WT mice, accompanied by suppression of DNA damage repair response; lastly, no aberrant proliferative or preneoplastic lesions were noted in DX-exposed livers. Overall, this study reveals, for the first time, that CYP2E1 is the main enzyme for DX metabolism at high dose and a primary contributor to DX-induced liver oxidative stress and associated cytotoxicity. High dose DX-induced genotoxicity may occur via CYP2E1-independent pathway(s), potentially involving impaired DNA damage repair.

Study of irradiation temperature effect on radiation-induced polymorphic transformation mechanisms in ZrO2 ceramics

The influence of high-dose exposure to heavy Xe23+ ions on the alteration in optical and structural properties, alongside the polymorphic transformation degree in polycrystalline ZrO2 ceramics is considered in the paper. The focus on such studies is primarily due to the possibility of obtaining new data on the mechanisms of radiation-induced damage associated with exposure to heavy ions comparable to fission fragments of nuclear fuel, alongside the comparison of the observed changes in the damaged layer properties with the polymorphic transformation processes characteristic of ZrO2 ceramics. Analysis of the obtained data on alterations in the optical and structural features of ceramics contingent upon irradiation conditions revealed that, the irradiation temperature leads to less pronounced structural degradation caused by deformation distortions of OI-Zr-OI, Zr-OII, Zr-OI/OII and Zr-OI bonds, as well as the accumulation of oxygen vacancies in the damaged layer. At the same time, using a set of research methods, it was determined that at irradiation temperatures above 700 K the processes of polymorphic transformations t – ZrO2→ c – ZrO2 caused by radiation and deformation effects are less pronounced, which results in the formation of inclusions in the form of t – ZrO2.

Effect of Age at Time of Irradiation, Sex, Genetic Diversity, and Granulopoietic Cytokine Radiomitigation on Lifespan and Lymphoma Development in Murine H-ARS Survivors.

Acute, high-dose radiation exposure results in life-threatening acute radiation syndrome (ARS) and debilitating delayed effects of acute radiation exposure (DEARE). The DEARE are a set of chronic multi-organ illnesses that can result in early death due to malignancy and other diseases. Animal models have proven essential in understanding the natural history of ARS and DEARE and licensure of medical countermeasures (MCM) according to the FDA Animal Rule. Our lab has developed models of hematopoietic (H)-ARS and DEARE in inbred C57BL/6J and Jackson Diversity Outbred (JDO) mice of both sexes and various ages and have used these models to identify mechanisms of radiation damage and effective MCMs. Herein, aggregate data from studies conducted over decades in our lab, consisting of 3,250 total-body lethally irradiated C57BL/6J young adult mice and 1,188 H-ARS survivors from these studies, along with smaller datasets in C57BL/6J pediatric and geriatric mice and JDO mice, were examined for lifespan and development of thymic lymphoma in survivors up to 3 years of age. Lifespan was found to be significantly shortened in H-ARS survivors compared to age-matched nonirradiated controls in all four models. Males and females exhibited similar lifespans except in the young adult C57BL/6J model where males survived longer than females after 16 months of age. The incidence of thymic lymphoma was increased in H-ARS survivors from the young adult and pediatric C57BL/6J models. Consistent with our findings in H-ARS, geriatric mice appeared more radioresistant than other models, with a lifespan and thymic lymphoma incidence more similar to nonirradiated controls than other models. Increased levels of multiple pro-inflammatory cytokines in DEARE bone marrow and serum correlated with shortened lifespan and malignancy, consistent with other animal models and human data. Of interest, G-CSF levels in bone marrow and serum 8-11 months after irradiation were significantly increased in females. Importantly, treatment with granulopoietic cytokine MCM for radiomitigation of H-ARS did not influence the long-term survival rate or incidence of thymic lymphoma in any model. Taken together, these findings indicate that the lifespan of H-ARS survivors was significantly decreased regardless of age at time of exposure or genetic diversity, and was unaffected by earlier treatment with granulopoietic cytokines for radiomitigation of H-ARS.